Despite decades of research, the hydrogen bond (H-bond) continues to attract sustained interest due to its remarkable diversity, its central role in molecular recognition processes and its complex cooperative behaviour. From experimental studies of a range of compounds containing functional groups relevant in organic (medicinal) chemistry, we measure a set of thermodynamic and spectroscopic parameters related to their H-bond strength with a reference H-bond donor or acceptor in solution. The differences observed in terms of behavior are in parallel investigated by quantum chemistry calculations. In recent years, our work within the framework of this thematic has in particular been devoted to the quantification of the H-bonding acidity (pK_AHY) of selected samples of organic compounds (e.g. silanols, see Figure below).

The objective of this axis is to make available to the scientific community a set of parameters describing in a precise and homogeneous manner the H-bond basicity and acidity of functional groups relevant in organic (medicinal) chemistry. The success of the pK_BHX database, developed about fifteen years ago, both at the industrial and academic levels, has clearly confirmed the lack of this type of data and their interest for a large chemistry community.

Publications

•    N. Galland, C. Laurence and J.-Y. Le Questel. J. Org. Chem., 87, 2022, 7264;
•    J. Graton, F. Besseau, A. Goupille and J.-Y. Le Questel. J. Mol. Struct., 1266, 2022, 133505.

The fluorination of organic compounds is of interest for the optimization of diverse properties (chemical, physical, pharmacological) of molecules and finds applications in most fields of the chemical industry. Paradoxically, studies aimed at rationalizing the influence of fluorine introduction in organic compounds are relatively few. Our work within the framework of this project is at the heart of this context. As part of a collaboration established for several years with the group of Prof. Bruno Linclau, at the University of Gent, specialized in the synthesis of fluorinated organic molecules, we study, through an approach combining experimental measurements and theoretical calculations, the influence of the introduction of fluorine atom (s) on the physicochemical properties (potential of interactions, lipophilicity ...) of original organic compounds derived from synthesis.

We have thus recently demonstrated from quantum chemistry calculations realised in our group and lipophylicitiy measurements carried out by NMR in our partner group (see figure below) how the (macroscopic) equilibrium constants K of fluorinated amide conformers in octanol and water are closely linked to their microscopic lipophilicity, which offers the possibility of indirectly determining the corresponding logp values. This relationship has opened up a new avenue for the rational optimisation of lipophilicity in fluorinated compounds.

Angew. Chem. Int. Ed. 61, (2022) e202114862

This work also makes it possible to characterize the lipophilicity potential of fluorinated organic compounds. Thus, through a systematic investigation of the modulation of lipophilicity following the introduction of different fluorination patterns, we were able to precisely quantify the effect of specific patterns. This work therefore offers the possibility of proposing avenues to rationally modulate the properties of organic molecules through the introduction of specific fluorination patterns (number and relative position of fluorine atoms).

This project presents applications in a large number of fields in chemistry. Our objective is, ultimately, to develop a set of tools and rules allowing a quantitative prediction and a detailed description of the effect of the introduction of fluorine atom(s) on fundamental physicochemical properties of molecules containing functionalities encountered in organic ligands with therapeutic aims.

Publications

•   B. Linclau, Z. Wang, B. Jeffries, F. Peron, J. Graton, R. J. Carbajo, D. Sinnaeve, J.-Y. Le Questel, J. S. Scott, E. Chiarparin. Angew. Chem. Int. Ed., 61,2022, e202114862
•   Z. Wang, G. Compain, M. Naskar, A. Goupille, L. Mtashobya, I. Murgia, J. Graton, J.-Y. Le Questel, and B. Linclau. ChemistryEurope, 2026, 4, e202500203
•   M. Naskar, Z. Wang, K. Patel, B. De Baets, A. Goupille, D. Sinnaeve, E. Renault, J.-Y. Le Questel and B. Linclau. Angew. Chem. Int. Ed., 2026, e3574068.

Despite the restrictions on the use of neonicotinoids in Europe due to their role in the decline of pollinating insects, their persistence in the environment continues to raise many questions in terms of toxicities, including potentially for mammals and humans, due to their accumulation and the possibility of cocktail effects.

In collaboration with Pr. Steeve Thany, neurobiologist and electrophysiologist at the University of Orléans, we elucidate the interactions of neonicotinoids and their recent derivatives (in particular sulfoxaflor, flupyradifurone) with 3D models of the extracellular ligand binding domain of nicotinic acetylcholine receptors (nAChRs).

We have therefore recently compared (i) the performance of molecular docking programs in predicting the interactions of these insecticides (see Figure below) (ii) developed force field parameters tailored to flupyradifurone, one of the latest compounds in this class to be developed by the agrochemical industry (iii) investigated their interactions with models of the human homomeric α7 nAChR and several mutants (Q79K in the D-loop, and E211N, E211P in the C-loop) of this nAChR.

Scatter plot illustrating the best RMSD values of docked poses against the respective system names, segregated by software for the semi-flexible docking method.The colored sections categorizes the systems based on the nature of the ligand (drug-like or neonicotinoid-like) and the type of receptor (AChBP or nAChR). Horizontal dashed lines represent RMSD thresholds that defines different levels of docking accuracy.
Ecotox. Env. Safety 281 (2024)116582

Ultimately, this research, carried out at various levels on nAChRs from bees and mammals, should contribute to a more detailed characterisation of the toxic effects of these compounds.

Publications

•   Cartereau, E. Taillebois, J.-Y. Le Questel and Steeve H. Thany. Int. J. Mol. Sci., 22 (2021) 9880; B. Selvam, E. Landagaray, A. Cartereau, A. D. Laurent, J. Graton, J. Lebreton, S. H. Thany, M. Mathé-       Allainmat, J.-Y. Le Questel. Bioorg. and Med. Chem. Lett. 80 (2023) 129124;
•   Z. Bouchouireb, S. H. Thany, J.-Y. Le Questel. J. Comput. Chem. 45 (2024) 377.
•   Z. Bouchouireb, D. Olivier-Jimenez, T. Jaunet-Lahary, S. H. Thany, J.-Y. Le Questel. Ecotox. Env. Safety 281 (2024)116582;
•   A. Cartereau, Z. Bouchouireb, S. Kaaki, F. Héricourt, E. Taillebois, J.-Y. Le Questel, S. H. Thany. Toxicology and Applied Pharmacology 492 (2024) 117123;
•   A. Cartereau, C. Veront, A. Cremades, P. Martin, R. Gojard, N. Galland, E. Taillebois, D. Togbé, J.-Y. Le Questel, Steeve H. Thany. Br. J. Pharmacol., 183 (2026) 3517–3537.

The prediction of protein-protein interactions and their use to develop new drugs is currently an important area of ​​research in medicinal chemistry. In the context of work carried out in collaboration with different teams of biologists, organic chemists and modellers, our work aims to describe and rationalize the interactions between inhibiting compounds of particular biological receptors in order to i) determine their binding sites, ii) explain experimental binding affinity data and/or iii) identify new inhibitors targeting a specific binding site of a macromolecule. To this end, virtual screening and classical molecular dynamics (MD) techniques are used systematically combined with the analysis tools. In this field several collaborations have been established with biologists, immunologists, oncologists or Computational chemists targeting several proteins like CD2-CD58 or hepatic lipase.

In the context of autoimmune diseases and allograft rejection, several projects have been developed in collaboration with Nantes Public Hospital in order to (i) identify alternative binding sites on the Human granzyme B (hGzmB). The hGzmB activity is triggered at a catalytic triad (His59, Asp103,Ser198), cleaving its specific substrates. Microsecond classical molecular dynamics simulations were devoted to exploring the structural dynamics of the hGzmB catalytic cycle in the presence of Ac-IEPD-AMC, a known substrate (active hGzmB), and Ac-IEPD-CHO, a known inhibitor (inactive hGzmB). We revealed an additional network of interactions involving Arg216, a residue located outside the conventional binding site. The binding of inhibitor Ac-IEPD-CHO to hGzmB prevents the Arg216-mediated interactions within the catalytic triad, thus preventing hGzmB activity. In silico Arg216Ala mutation confirms the role of Arg216 in enzyme activity, as the substrate Ac-IEPD-AMC failed to bind to the mutated hGzmB. Importantly, as Arg216 is not conserved amongst the various granzymes, the current findings can be a major step to guide the design of hGzmB specific therapeutics.

Another direction to this fruitful collaboration is to disrupt the T-cell leukemia/lymphoma 1A (TCL1A) protein dimerization to induce tolerance.

Publications

• N. Tripathi, R. Danger, M. Chesneau, S. Brouard, A. D. Laurent J. Mol. Graph. Model. 114, 108167 (2022)
• N. Tripathi, L. Leherte, D.V. Vercauteren, A.D. Laurent, J. Comput. Aided Mol. Des., 35, 33--353 (2021)
• W. Dijk PhD, M. Di Filippo, S. Kooijman, R. van Eenige, A. Rimbert, A. Caillaud, A. Thedrez, L. Arnaud, A. Pronk, D. Garçon, T. Sotin, P. Lindenbaum, E. Ozcariz Garcia, J.-P. Pais de Barros, L. Duvillard, K. Si-Tayeb, N. Amigo, J.-Y. Le Questel, P. C.N. Rensen, C. Le May, P. Moulin, B. Cariou Circulation 87, 2022, 7264